This application requests support for a Keystone Symposia meeting entitled Mechanism and Biology of Silencing, organized by Drs. Elisa Izaurralde, Victor Ambros, and V. Narry Kim, which will be held in Monterey, California from March 20-25, 2011. Mechanisms of gene regulation mediated by small RNAs-including microRNAs, siRNAs, and piRNAs-play critical roles in processes central to the growth and metabolism of eukaryotic cells as well as to the development and homeostasis of tissues and organs in humans. Genetic, molecular, and biochemical research into RNA silencing, employing model organisms as well as human cells and tissues, continues to reveal new insights and understanding of processes fundamental to human development and disease. The focus of the Keystone Symposia meeting on Mechanism and Biology of Silencing is on basic research including molecular mechanisms, evolution, and the biological role of silencing in a broad sense across all species. The aim of this meeting is to transcend the current diversity and complexity of information about gene silencing and, in so doing, to discern unifying principles that will serve as a springboard for future research and allow investigators to harness these principles and mechanisms for gene discovery and therapeutic applications. The meeting will seek to unite a field increasingly specialized by organism type and biological function, and will stress broad themes shared by small-RNA silencing pathways in plants, animals, and fungi. PROJECT NARRATIVE: The regulation of gene expression by small noncoding RNAs (gene silencing) is ubiquitous in eukaryotes and central to diverse cellular and organismal processes that underlie human health, including development, homeostasis, genomic integrity, and the origination and development of disease. It has become increasingly apparent that the molecular mechanisms and biological roles of gene silencing processes are exceedingly diverse and complex. The Keystone Symposia meeting on Mechanism and Biology of Silencing is designed to identify unifying mechanistic principles and to stimulate collaborative, interdisciplinary approaches to address unanswered questions as well as to develop therapeutic applications of gene silencing.